The primary objective of this long-standing grant is understanding the molecular and cellular mechanisms underlying neuronal production and migration during development of the cerebral cortex. Our basic strategy is to continue parallel studies of these early developmental events in mice and macaque monkey to uncover evolutionary adaptations leading to the expansion and elaboration of this structure. Our hypothesis is that most recently acquired traits are particularly vulnerable to genetic mutations and environmental influences. In particular, the longer cell cycle and longer migratory pathways and more complex connectivity in primates predispose congenital malformations during prenatal life. In Specific Aim #1 we have developed new in vitro and in vivo approaches to analyze regulation of neuronal production and phenotype specification. We propose to examine the mode and pattern of proliferation of living neural stem cells using multi-photon microscopy, both in vivo and slice preparations. These studies will test the roles of several morphoregulatory molecules in regulation of cell cycle and diversification into neural and glial cell lines. The transition of neuronal stem cells from the active stage to dormancy will be compared with the capacity of adult stem cells in the subependymal zone of mice and macaque's under normal, genetically altered and environmentally challenged conditions. Specific Aim #2 is focused on neuronal migration. We will examine interneuron migration from the ganglionic eminence of the ventral telencephalon and their integration with the radial columns of neurons derived from the dorsal telencephalon in the normal and genetically perturbed forebrain. A major emphasis will be on the possible effect of ultrasound on neuronal migration rate and placement in both murine and primate cerebral cortex, as this study may have important biomedical implications. Emphasis on the early aspects of neuronal production and proper placement in mammalian species will provide new insight into the pathogenesis of genetic and acquired cortical malformations affecting higher brain function, and will also have direct implications for assessing the prospect of stem cell therapy. The proposed studies are even more pressing given the recent increase in incidence of developmental disorders of higher brain functions such as autism, childhood epilepsy, developmental dyslexia and mental retardation, possibly attributable to neuronal misplacement during formation of the cerebral cortex. [unreadable] [unreadable]